Opiates are the most powerful analgesic agents presently available. The general goal of the proposed research is to elucidate the circuitry underlying opiate actions that produce analgesia. This proposal is specifically focussed on the mechanisms of opiate analgesia at the level of the brainstem. The rostral ventromedial medulla (RVM) is involved in opioid-sensitive mechanisms that underlie brainstem control of nociceptive transmission. Opiate receptors and endogenous opioid peptides are found in this region, and microinjection of opiate agonists into RVM suppresses behavioral responses to noxious stimulation. Two classes of putative nociceptive modulating neurons have been identified in the RVM. Off-cells, which are thought to suppress nociceptive transmission, are activated by morphine. On-cells, which appear to facilitate nociceptive processing, are depressed by morphine. Other RVM neurons, neutral cells, are unaffected by morphine. We propose to use intracranial microinjection techniques, behavioral tests of nociceptive responsiveness, single unit recording and microiontophoresis to investigate the neurotransmitters involved in opiate control of the activity of physiologically-identified RVM neurons. We plan to investigate the actions of morphine, norepinephrine, serotonin and excitatory amino acids. We are particularly interested in determining how cells containing these transmitters contribute to the antinociceptive action of opiates. Hopefully, by increasing knowledge of how opiates produce analgesia, new drugs or pharmacological strategies can be devised to produce analgesia more selectively.